Focus on HSP70:

Why this heat shock protein has the potential to reshape the future of diseases caused by protein misfolding

HSP70 heat-shock protein
See how HSP70 functions

Cellular stress within the body can be caused by a number of sources and lead to issues including: protein misfolding and aggregation; accumulation of misfolded proteins; and lysosomal permeabilization and instability.1,2

Heat shock proteins, specifically HSP70, have a critical role in protein-folding rescue, either by preventing misfolding or by promoting refolding, thereby restoring protein function.3

HSP70 heat-shock protein
Proteostasis

Proteostasis is an important function critical to maintaining cellular health in the body

Normal proteostasis ensures that proteins are produced and folded appropriately before they are trafficked to precise locations. It also acts to ensure that abnormal or excess proteins are degraded to prevent the accumulation of unwanted products.4,5

Correct protein folding icon

Building proteins within the cell is a complex process involving protein folding. A protein must fold into a specific 3-dimensional conformation to gain proper function. Because of the critical role proteins play, incorrect folding can result in diseases such as Alzheimer's and Parkinson's.6


Protein-misfolding icon

Protein misfolding may occur due to genetic or environmental factors and often leads to loss of function. Misfolded proteins may accumulate, form intermediate oligomers or fibrils, and, eventually, mature aggregates, all of which can be toxic to the cell.3,7

Protein misfolding underlies a large number of chronic diseases, including neurodegenerative and lysosomal storage diseases7-9

Protein misfolding

Protein aggregation

Neurodegenerative diseases

  • Inclusion body myositis
  • Amyotrophic lateral sclerosis
  • Parkinson’s disease
  • Huntington's disease
  • Alzheimer's disease

Lysosomal dysfunction

Lysosomal storage diseases

  • Niemann-Pick disease type C
  • Gaucher disease
  • Sandhoff disease
  • Fabry disease
  • Metachromatic leukodystrophy

Disease definitions

Inclusion body myositis is an acquired progressive muscle disorder that becomes apparent during adulthood and in most cases is characterized by progressive weakness and degeneration (atrophy) of the muscles, especially those of the arms and the legs.10

Parkinson’s disease is a neurodegenerative disorder that affects predominantly dopamine-producing (“dopaminergic”) neurons in a specific area of the brain called the substantia nigra.11

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurological disease. Sometimes called Lou Gehrig's disease, ALS belongs to a group of disorders known as motor neuron diseases.12

Huntington's disease is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. It deteriorates a person’s physical and mental abilities, usually during their prime working years, and has no cure.13

Alzheimer’s disease is a type of irreversible, progressive brain disease that attacks and destroys brain cells, which results in a loss of memory and other essential cognitive functions.14

Niemann-Pick disease type C is a rare, progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (such as lipids) inside of cells. This leads to the abnormal accumulation of these substances within various tissues of the body, including brain tissue. The accumulation of these substances damages the affected areas.15

Gaucher disease is one of the most common lysosomal storage disorders. It is a genetic disorder where fat-laden Gaucher cells build up in areas like the spleen, liver, and bone marrow. A person will get Gaucher disease if both parents are carriers of the disease.16

Sandhoff disease is a rare, inherited lipid storage disorder that progressively destroys nerve cells in the brain and spinal cord. It is caused by a deficiency of the enzyme beta-hexosaminidase, which results in the harmful accumulation of certain fats (lipids) in the brain and other organs of the body.17

Fabry disease is a rare genetic disorder that prevents the body from making an enzyme called alpha-galactosidase A. This enzyme is responsible for breaking down a type of fat called globotriaosylceramide (Gb3 or GL-3) into building blocks that the body's cells can use.18

Metachromatic leukodystrophy is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system.19

Heat shock proteins are the body’s natural response to protect cells, triggered when a cell is under stress

Heat shock proteins exist in normal circumstances, but their production is induced by stress—and they play a particularly important role in protecting cells exposed to stress.20

Heat shock proteins play a critical role in protein-folding rescue

Heat shock proteins constitute part of the molecular chaperone system of the cell and play a critical role in protein-folding rescue21

Heat shock proteins are involved in several processes, such as assisting other proteins to achieve the correct conformation, and preventing protein misfolding and aggregation. When the heat shock response is activated, increased heat shock protein expression is induced.

The heat shock protein system constitutes the central element of proteostasis

The heat shock protein system constitutes a central component of cellular protein quality control functions and proteostasis22

Heat shock proteins are classified according to their molecular weight and include families of small HSPs, HSP40, HSP60, HSP70, HSP90, HSP110, and TCP-1 ring complex (TRiC).4

See how HSP70 functions

View Transcript

The importance of proteostasis—the proper formation, folding, trafficking, and degradation of proteins—within the human body cannot be overlooked.4,5

Protein misfolding can lead to protein aggregation, resulting in neuromuscular and neurodegenerative diseases. Protein misfolding can also lead to lysosomal dysfunction and inefficient lipid trafficking, resulting in the manifestation of lysosomal storage diseases.7-9

Heat shock proteins play a key role in maintaining proteostasis within the human body.3

Heat shock proteins, or HSPs, are the body’s natural response triggered when a cell is under stress.20

As molecular chaperones, they limit damage and facilitate recovery.22

When the cell is under stress, heat shock factor 1 amplifies the production of heat shock proteins, like HSP70.23

HSP70 guards cellular function and integrity during the heat shock response through three key mechanisms1,21,22:

  • It repairs and refolds damaged proteins and corrects misfolding allowing proteins to perform their normal functions.
  • It prevents protein aggregates to correct protein folding or alternatively facilitates degradation of the aggregates, with the help of co-chaperones.
  • It promotes lysosomal function by chaperoning key enzymes to the lysosomal membrane, where they can resume their normal function.

In summary, HSP70 is a molecular chaperone that guards cellular function and integrity through three key mechanisms.1,21

HSP70 is a key focus of Orphazyme’s research and has potential as a therapeutic target and biomarker for diseases caused by protein misfolding.21

HSP70 Location

HSP70 could be the foundation for addressing protein-misfolding diseases

What is the function of HSP70?1,22,24

HSP70 is a key chaperone in protein homeostasis and promotes lysosome membrane stability and integrity. HSP70 recruits and forms complexes with co-chaperones to mark proteins for degradation and to guide them to the proteasome or, for larger aggregates, to the autophagy–lysosome system.

How does HSP70 respond to cellular stress?21,22

HSP70 production is regulated by key transcription factors known as heat shock factors (HSFs). In chronic disease, the heat shock response may be insufficient to cope with prolonged exposure to a proteotoxic environment. Under times of stress, HSF-1 amplifies the transcription of HSP70 genes and the production of HSP70 proteins.

The resulting increased levels of HSP70 results in a heightened response to the stress, protecting cellular proteins from misfolding errors.

By focusing on HSP70 and its role in correcting protein misfolding, protein aggregation, and lysosomal dysfunction, a number of conditions can be addressed1,21,22

HSP70 guards cellular function and integrity during the heat shock response through 3 key mechanisms:

HSP70 functions HSP70 functions
HSP70 prevents and corrects protein-misfolding

Prevents and corrects
protein misfolding

This lets proteins perform
their normal functions

HSP70 prevents and removes protein aggregates

Prevents and removes
protein aggregates

This facilitates proper protein
folding or protein degradation

HSP70 promotes lysosomal function

Promotes lysosomal function

This allows lipids and other key enzymes to
be chaperoned to the lysosomal membrane

Orphazyme is investigating the role of HSP70 and its effects on protein misfolding

By focusing on HSP70, we hope to be able to address a number of protein-misfolding conditions and how they may be treated in the future.

See how we’re moving forward
Orphazyme is investigating the role of HSP70

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